ABSTRACT ? ARTFL LEFFTDS Longitudinal FTLD: GENETICS CORE The overarching goal of the Genetics Core is the accurate and timely generation, annotation, interpretation and sharing of state-of-the art genetic data on all frontotemporal lobar degeneration (FTLD) patients and blood relatives enrolled in ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) to support FTLD research within and outside of the ALLFTD Program. Genetic characterization of this unique cohort is critically important to test hypotheses and interpret research findings obtained in the other ALLFTD Cores and Projects and will be invaluable to future FTLD gene discovery efforts within the larger research community. The work proposed in this Core is highly complementary and non-overlapping with currently ongoing NIH-funded FTLD sequencing efforts, which will be leveraged to enhance the genetic characterization of our participant cohorts. More than 1,100 unique individuals have been enrolled in ARTFL and LEFFTDS since their inception in 2014 and an additional 1,600 unique individuals are expected to be enrolled as part of the ALLFTD protocol. Consequently, DNA of at least 2,700 individuals will be available for genetic studies, making this an unprecedented resource. Most notably, on all 2,700 subjects, the Genetics Core will: generate genome-wide single nucleotide variant (SNP) data; perform targeted mutation screening of ~300 neurodegenerative disease genes; determine presence or absence of causal mutations in known disease genes; and integrate genetic data in the form of polygenic risk scores (PGRS) for downstream analyses in the Projects. These important goals are achieved through the following Specific Aims: 1) Perform genetic analyses to determine ethnicity and relatedness between ALLFTD participants. Genotyping using the Infinium Omni2.5Exome-8 Kit will be performed in all newly ascertained ALLFTD participants (n=1,600) and combined with previously obtained genotype data (n=1,100) to determine the ethnicity and relatedness between ALLFTD participants, to call copy-number variants (CNVs) and to calculate PGRS; 2) Perform targeted mutation analysis in ALLFTD participants. We will follow an efficient, step-wise, approach to genetically characterize ALLFTD participants, including C9orf72 and ATXN2 repeat expansion testing, targeted gene sequencing of ~300 neurodegenerative disease genes with sequence validation and manual curation of observed variants using American College of Medical Genetics and Genomics guidelines, and whole-genome sequencing and analysis of newly ascertained genetically unexplained familial FTLD patients; and 3) Generate PGRS for ALLFTD participants. Distinct datasets from published genome-wide association studies will be used to generate PGRS in study participants for use in the Projects, including PGRS for individual neurodegenerative diseases and PGRS that reflect related pathologies such as immunological disorders. As our sample size increases we will further derive PGRS from genomic data generated as part of ALLFTD, especially for FTLD clinical subtypes.